From the Cardiology Branch, National Heart, Lung, and Blood Institute,
Bethesda, Md.
Methods and Results—In 14 patients with coronary
atherosclerosis and 5 with risk factors, we tested
femoral vascular endothelial function with
acetylcholine and substance P and
endothelium-independent function with sodium
nitroprusside before and after intravenous aspirin. Drugs
were infused into the femoral artery, and Doppler flow velocity was
measured. Acetylcholine-induced but not substance P–or sodium
nitroprusside–induced vasodilation was lower in patients with
atherosclerosis than in those with only risk factors.
Aspirin had no baseline effect but improved acetylcholine-mediated
vasodilation only in patients with atherosclerosis; at
the peak dose, acetylcholine-mediated femoral vascular resistance index
was 19±5%, P=.002 lower. There was a correlation
between the baseline response to acetylcholine and the magnitude of
improvement with aspirin (r=.5, P=.05).
Thus, patients with a depressed response to acetylcholine had greater
improvement with aspirin, and vice versa. The presence of
atherosclerosis was an independent determinant of
improvement with aspirin. Aspirin had no effect on the responses to
either substance P or sodium nitroprusside.
Conclusions—Cyclooxygenase-dependent,
endothelium-derived vasoconstrictor release modulates
acetylcholine-induced peripheral vasodilation in patients
with atherosclerosis. Improvement of
endothelial dysfunction with aspirin may improve
vasodilation, reduce thrombosis, and inhibit progression of
atherosclerosis and provides a
pathophysiological basis for the beneficial effects
of aspirin in atherosclerosis.
In this study, we tested the hypothesis that the beneficial
effects of aspirin in patients with atherosclerosis may
be due, at least in part, to improvement of endothelial
dysfunction. For this purpose, we investigated whether an
endothelium-derived
cyclooxygenase-dependent constricting factor
contributes to the abnormal acetylcholine-mediated dilation in patients
with atherosclerosis.
Another group of 10 patients with coronary
atherosclerosis was studied to test the reproducibility
of administration of the vasodilators on two successive occasions in
the femoral circulation. Informed consent was obtained from all
subjects, and the protocol was approved by the National Heart, Lung,
and Blood Institute Ethical Review Board.
Measurement of Femoral Blood Flow Velocity
Study Protocol
After a 15-minute recovery period and return to baseline, 1 g
aspirin lysine (Aspegic injectable, Synthelabo Groupe) was infused
intravenously over a 10-minute period in the study
patients, and dextrose 5% was given to control patients. This was
followed 15 minutes later by repeat infusions of acetylcholine,
substance P, and sodium nitroprusside. Peak flow velocity and blood
pressure measurements were made after each intervention.
Statistical Analysis
Effect of Aspirin
When the response to aspirin of all 19 patients was examined, there was
a significant correlation between the percent change in FVRI with
acetylcholine (300-µg/min dose) and the magnitude of improvement in
FVRI with aspirin, R=.50, P=.05, indicating that
patients with an initially lower response to acetylcholine had greater
improvement with aspirin than those with a higher vasodilator response
to acetylcholine. The latter had no significant change with
aspirin.
Multivariate analysis was performed in all 19
patients to examine whether the presence of angiographic
atherosclerosis or any risk factor for
atherosclerosis (age, sex, serum
cholesterol level, HDL level, ejection fraction, presence
of hypertension, diabetes, family history of coronary artery
disease, or smoking history) determined the magnitude of the effect of
aspirin on the acetylcholine response. The only significant predictor
of improvement in the FVRI with acetylcholine after aspirin was the
presence of angiographic atherosclerosis,
r=.60, P=.005.
In contrast to its effect on the acetylcholine response in patients
with atherosclerosis, aspirin produced no change in the
vasodilator responses to either substance P or sodium nitroprusside in
either patients with or those without atherosclerosis
(Figs 2
Reproducibility of Vasodilator Infusions
Release of vasoconstrictor prostanoids by acetylcholine, an
endothelium-dependent agonist that also releases nitric
oxide and other vasodilators, has been demonstrated in animal
studies.11 12 13 14 15 16 17 Endothelial
impairment in rat aortic rings was accompanied by increased
production of thromboxane A2
and prostaglandin F2
Multivariate analysis failed to identify a
single risk factor or a combination of risk factors that were
associated with the magnitude of improvement of the acetylcholine
response with aspirin. However, the presence of
atherosclerosis was an independent predictor of
improvement with cyclooxygenase inhibition.
Patients with atherosclerosis also had a lower
vasodilator response with acetylcholine compared with patients with
risk factors but without atherosclerosis in this study
and also compared with patients without risk factors studied in a
previous investigation.35 Taken together, these
findings suggest that patients with worse endothelial
function, as indicated by a greater depression of the acetylcholine
response, had greater production of constrictor
prostaglandins. Thus, as atherosclerosis
develops in patients with risk factors and endothelial
dysfunction progresses, there appears to be significant
production of constrictor substances in response to muscarinic
receptor stimulation.
Our study also demonstrated that the response to the nonmuscarinic
endothelium-dependent vasodilator substance P in
patients with atherosclerosis did not correlate with
the response to acetylcholine, a finding observed previously in the
coronary vasculature.38 39 Because the
second messenger pathways from the activation of tachykinin and
muscarinic receptors are believed to be the
same,40 it is possible that the differences
observed are secondary to differential dysfunction of the
endothelial surface receptors by factors that produce
atherosclerosis. There was little evidence for either
constrictor or dilator prostaglandin production in
response to substance P, unless both were generated in quantities that
resulted in no net vascular effect. Thus, the depression in the
acetylcholine response observed in patients with intact substance
P–mediated vasodilation may also be due to stimulation of
vasoconstrictor prostanoids by acetylcholine, in addition to factors
mentioned above.
We did not attempt to characterize the nature of the vasoconstrictor
released in response to acetylcholine in patients with
atherosclerosis in this study. Possible mediators
include prostaglandin F2
Limitations
Although we have assumed that the beneficial effects of aspirin are
most likely due to its effects as a cyclooxygenase
inhibitor, it is possible that there may be as yet
unidentified mechanisms that may produce the observed changes.
Implications
Received June 5, 1997;
revision received October 20, 1997;
accepted October 27, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Aspirin Improves Endothelial Dysfunction in Atherosclerosis
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The beneficial effects of
aspirin in atherosclerosis are generally attributed to
its antiplatelet activities, but its influence on
endothelial function remains uncertain. We hypothesized
that a cyclooxygenase-dependent constricting factor
contributes to the endothelial dysfunction in
atherosclerosis and that its action can be reversed
by aspirin.
Key Words: endothelium-derived factors • aspirin • atherosclerosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The beneficial
effects of aspirin in reducing acute coronary and
cerebrovascular events such as unstable angina, myocardial infarction,
sudden cardiac death, and stroke have been attributed largely to its
antiplatelet action and to its effects on
thromboxane.1 2 3 Whether aspirin has
a more profound action, particularly on endothelial
function, which is pivotal in modulating tone, thrombotic potential,
and atherosclerotic tendency of the blood vessel wall, remains a
subject of speculation. The endothelium modulates
vascular smooth muscle tone by paracrine release of dilating and
constricting compounds that are secreted in response to a variety of
physiological and pharmacological
stimuli.4 5 6 Dilating factors include nitric
oxide or a compound closely related to it,7 8
endothelium-derived hyperpolarizing
factor,6 and vasodilator
prostaglandins, such as
prostacyclin.9 Constricting agents released by
the endothelium include
endothelin,10 constricting
cyclooxygenase products such as
thromboxane A2,
prostaglandin F2
, and superoxide
anion.11 12 13 14 15 16 17 Acetylcholine, a commonly used probe
for testing endothelial function in humans, causes
endothelium-dependent smooth muscle vasodilation, which
is believed to be caused largely by release of nitric oxide and
endothelium-derived hyperpolarizing
factor.4 5 6 7 Acetylcholine-induced vasodilation is
diminished in the conductance and resistance vessels of patients with
atherosclerosis and in those with risk factors for
atherosclerosis, such as
hypercholesterolemia, hypertension, diabetes,
aging, and smoking, and in patients with congestive heart
failure.18 19 20 21 22 23 24 25 This abnormality is usually
attributed to decreased activity of endothelium-derived
relaxing factors, but recent studies show that an abnormal response to
acetylcholine in congestive heart failure and diabetes may be due to
production of a cyclooxygenase-dependent
vasoconstricting factor.26 27 28 29 30
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients
The study was performed at least 2 hours after patients
underwent diagnostic cardiac
catheterization for diagnosis of suspected or confirmed
coronary artery disease. Femoral vascular
endothelial function was studied in 19 patients who had
angiographic evidence of coronary
atherosclerosis (n=14) or had one or more risk factors
for atherosclerosis (n=5). The risk factors were
defined as presence of hypertension (arterial blood
pressure >140/90), diabetes mellitus, history of past or continued
smoking, cholesterol level >240 mg/dL, and age >60 years
(Table 1
). None had significant left
ventricular dysfunction (ejection fraction by radionuclide
ventriculography 
40%) or evidence of heart failure. All cardiac
medications were withdrawn at least 48 hours before the study, and
aspirin and other cyclooxygenase
inhibitors were discontinued for at least 7 days before
the study.
View this table:
[in a new window]
Table 1. Patient Characteristics
A 6F angiographic multipurpose A2 (Cordis, Inc) catheter was
introduced 1 cm beyond the end of a 7F femoral artery sheath. A
0.018-in Doppler flow wire (Cardiometrics, Inc) was introduced
through the catheter 1 cm beyond the catheter tip to obtain an adequate
flow velocity signal throughout the study. Drugs were infused through
the sheath 
2 cm below the tip of the Doppler wire. A femoral
angiogram was performed to exclude obstructive disease in the femoral
circulation. The average peak velocity during each intervention was
recorded.31 Because diameter measurements
were not made at the level of the Doppler wire with each
intervention, we calculated the femoral vascular resistance index
(FVRI, mm Hg · cm-1 ·
s-1) as the mean arterial pressure
divided by femoral blood flow velocity. To exclude any significant
changes in femoral artery diameter at the site of the flow wire during
conditions of increased blood flow, in a preliminary study using serial
angiography, we measured femoral artery diameter at the site of the
flow wire during administration of 300 µg/min acetylcholine and 40
µg/min sodium nitroprusside in 24 patients. There was no significant
alteration in femoral arterial diameter at the site of the
flow wire during these drug infusions: baseline, 5.1±0.9 mm;
acetylcholine, 5.1±0.9 mm; and sodium nitroprusside,
5.1±0.9 mm (all P=NS compared with baseline). We have
also measured femoral diameter using ultrasound in the midsection of
the femoral artery in a preliminary study. No constriction was observed
in femoral diameter with acetylcholine in patients with
atherosclerosis or its risk factors.
After baseline measurement of flow velocity and mean
arterial pressure, 2-minute infusions of acetylcholine at
150 and 300 µg/min were given. This was followed after a 10-minute
period by administration of substance P at 20 and 40 pmol/min for 3
minutes each. The order of acetylcholine and substance P was
randomized. Ten minutes after recovery and return to baseline values,
sodium nitroprusside was administered at 40 µg/min for 3 to 4
minutes.
Data are expressed as mean±SEM. Means were compared by
paired or unpaired Student's t test, as appropriate, and
discrete data were compared by the 
2 test. All
probability values are two-tailed. The global effects of aspirin on two
doses of acetylcholine and substance P were compared by ANOVA for
repeated measures.32 Multiple stepwise regression
analysis33 was performed to test whether
the magnitude of change in the response to the peak dose of
acetylcholine with aspirin was related to age, sex, presence of
hypertension, diabetes, cigarette use, cholesterol level,
HDL level, family history of coronary artery disease, or the
presence or absence of angiographic
atherosclerosis.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Vascular Responses in Patients With and Without
Atherosclerosis
Acetylcholine, substance P, and sodium nitroprusside
produced progressive microvascular dilation both in patients with
atherosclerosis and in those with risk factors for
atherosclerosis. However, the response to acetylcholine
but not to substance P or to sodium nitroprusside was significantly
blunted in patients with atherosclerosis (Fig 1). Thus, at the peak dose of
acetylcholine, FVRI was 58±4% lower than baseline in those with risk
factors and 46±5% (P=.04) lower in those with
atherosclerosis. There was no change in
arterial blood pressure during the infusions.
View larger version (15K):
[in a new window]
Figure 1. Effects of acetylcholine (left), substance P
(middle), and sodium nitroprusside (right) in patients with
atherosclerosis and those with risk factors but no
atherosclerosis. FVRI indicates femoral vascular
resistance index (mm Hg · cm-1 ·
s-1).
Fifteen minutes after intravenous aspirin, there was
no significant change in systemic arterial blood pressure
or FVRI in either group of patients. Aspirin significantly enhanced the
vasodilation in response to acetylcholine in patients with
atherosclerosis, but there was no change in those
without atherosclerosis (Figs 2 and 3).
At the highest dose of acetylcholine, FVRI was 19% lower in patients
with atherosclerosis (P=.002), but the 1%
change in those with risk factors only was not significant (Figs 2 and 3).
View larger version (14K):
[in a new window]
Figure 2. Effect of aspirin on response to acetylcholine
(left), substance P (middle), and sodium nitroprusside (right) in 14
patients with atherosclerosis. Abbreviation as in Fig 1 
.
View larger version (14K):
[in a new window]
Figure 3. Effect of aspirin on response to acetylcholine
(left), substance P (middle), and sodium nitroprusside (right) in 5
patients with risk factors but without angiographic
atherosclerosis. Abbreviation as in Fig 1 . and 3). At the peak dose of substance P, aspirin produced a
4.5%, P=.26 decrease in FVRI in patients with
atherosclerosis and a 16%, P=.12 increase
in those with risk factors. Similarly, with sodium nitroprusside,
aspirin produced a 1%, P=.95 reduction in FVRI in those
with atherosclerosis and a 6%, P<.33
reduction in those without atherosclerosis (Figs 2 and 3).
To examine whether two successive infusions of acetylcholine and
substance P produced similar vasodilation in the femoral circulation,
we tested responses to them in 10 patients before and after dextrose
5% (Table 2). The effect of the first
infusion of both endothelium-dependent vasodilators was
reproducible during the second infusion after dextrose 5%.
View this table:
[in a new window]
Table 2. Reproducibility of Changes in Femoral Vascular
Resistance Index With Acetylcholine and Substance P in Control Patients
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The major finding of this study is that aspirin modulates
acetylcholine-induced peripheral vasodilation in patients
with atherosclerosis, possibly via inhibition of one or
more cyclooxygenase-dependent vasoconstrictors.
There is no evidence for significant production of either
vasodilator or vasoconstrictor prostaglandins in response
to the nonmuscarinic endothelium-dependent vasodilator
substance P or with the endothelium-independent dilator
sodium nitroprusside. , an
abnormality that was normalized by inhibitors of
cyclooxygenase or prostaglandin
endoperoxide.12 13 14 27
Acetylcholine-induced, endothelium-dependent
contractions of aortic strips from spontaneously hypertensive rats and
pulmonary arterioles of rabbits were inhibited by
indomethacin.13 14 Release of
acetylcholine-mediated, cyclooxygenase-dependent,
endothelium-derived vasoconstrictor substances was
observed in the canine model of heart failure,30
a finding that was subsequently corroborated in the
peripheral circulation of patients with congestive heart
failure. Cyclooxygenase inhibition with
indomethacin increased acetylcholine-mediated forearm
vasodilation by 39% in patients with congestive heart failure but not
in normal subjects.26 29 Despite demonstration of
acetylcholine-mediated release of vasoconstrictor
prostaglandins in animal models of hypertension and
diabetes,13 14 27 28 34 most human studies have
failed to show any effect of cyclooxygenase
inhibitors on acetylcholine-mediated forearm vasodilation
in hypertensive and diabetic patients,35 36
although one study recently demonstrated release of constrictor
prostaglandins with acetylcholine in the forearm
circulation of patients with hypertension.37 In
agreement with these reports, patients with risk factors but without
atherosclerosis in our study group also had no apparent
effect with aspirin, and none of our patients had evidence of
congestive heart failure. To the best of our knowledge, our study is
the first demonstration of acetylcholine-mediated constrictor
prostaglandin production in response to
acetylcholine in patients with atherosclerosis. ,
thromboxane A2, and related
constrictor prostaglandins.11 12 13 14 15 16 17 A
more provocative and recently elucidated antioxidant action
of cyclooxygenase inhibitors may be an
important mechanism for the observed effect of aspirin in this study.
Salicylic acid is known to scavenge both oxygen free radicals and
hydroxyl radicals in activated
granulocytes,41 and acetylcholine-mediated
constriction due to cyclooxygenase-dependent
superoxide anion production has been demonstrated in several
animal models.16 42 43 44 45 Superoxide anions avidly
metabolize nitric oxide to higher, biologically inactive nitrogen
oxides and are believed to be the primary mechanism underlying the
reduced bioavailability of nitric oxide in
atherosclerosis. Thus, it is possible that as
endothelial dysfunction progresses in
atherosclerosis, acetylcholine but not substance P
promotes increased production of
cyclooxygenase-dependent free radicals, which in
turn inactivate nitric oxide and reduce its
bioavailability.
The relatively small group of patients without
atherosclerosis but with risk factors included in this
study may have obscured a potential effect of aspirin in this
population. Also, there may be other risk factors that produce
endothelial dysfunction, such as homocysteinuria, that
were not measured in these patients. However, our findings are
compatible with the lack of effect of
cyclooxygenase inhibitors on the
acetylcholine response in patients with hypertension or
diabetes.35 36 Furthermore, the inverse
correlation between baseline vasodilation with acetylcholine and the
magnitude of improvement with aspirin suggests that if the
acetylcholine response in subjects with risk factors reduces to the
level observed in patients with atherosclerosis, then
aspirin is also likely to produce improvement.
The clinical implications of our findings are likely to be
important for patients with atherosclerosis, because
there is a relationship between the response to pharmacological
stimulation of the vascular endothelium with
acetylcholine and the physiological vasodilation in
response to metabolic stresses such as atrial
pacing,46 47 mental
stress,48 exercise,49 and
hyperemia50 ; thus, patients with an
abnormal response to acetylcholine also tend to have abnormal
vasodilation in response to these physiological
stimuli. Whether there is a contribution from
endothelium-dependent constrictor factor release to the
abnormal flow-mediated vasodilation observed in atherosclerotic blood
vessels, which has hitherto been believed to be largely due to reduced
nitric oxide activity, needs further investigation. Moreover, it is
conceivable that aspirin may also improve
physiological vasodilation in this population, a
hypothesis that requires further evaluation. Finally, if the effect of
aspirin on improving endothelial dysfunction is
mediated by reduction in oxidant stress by inhibition of
cyclooxygenase-dependent free radical
production in the vessel wall, it is likely that over the long
term, increased nitric oxide bioavailability in atherosclerotic blood
vessels will reduce their thrombogenic tendency and decelerate
progression of plaque development.51 52 Thus,
demonstration of improved endothelium-dependent
vasodilation with aspirin provides a novel
pathophysiological basis for its beneficial effects
in atherosclerotic patients, which to date has been largely attributed
to its antithrombotic effects.
Footnotes
Reprint requests to Arshed A. Quyyumi, MD, Cardiology Branch, NHLBI, 10 Center Dr, MSC 1650, Bldg 10, Room 7B15, Bethesda, MD 20892-1650.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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